Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics

Definitions

• This invention relates to the use of certain 4-phenylpiperidines in the treatment of pruritus, including allergic dermatitis and atopy, in animals and humans.
• pruritus is a common dermatological symptom which can give rise to considerable distress, in both humans and animals. Pruritus is often associated with inflammatory skin disease which can commonly be caused by hypersensitivity reactions (such as reaction to insect bites e.g. flea bites, or to environmental allergens such as house dust mite or pollen), bacterial and fungal infections of the skin or ectoparasite infections. Previous treatments for pruritus include the use of corticosteroids and antihistamines, however both have undesired side effects. Other therapies include the use of essential fatty acid dietary supplements which are slow to act and offer only limited efficacy against allergic dermatitis.
• WO84/00889 and U.S. Pat. No. 4,181,726 disclose the use of the opioid antagonist naloxone in the treatment of pruritus, however naloxone has not been commercially exploited for the control of pruritus, and there is a continuing need for a cheap and effective remedy.
• Certain 1,3,4-trisubstituted 4-aryl-piperidine derivatives are disclosed in GB-A-1525584 as potent narcotic antagonists which also display analgesic properties. These compounds are also claimed in EP-A-0287339 as opioid antagonists which block the effect of agonists at the mu or kappa receptors, having potential utility in treating a variety of disorders associated with these receptors such as eating disorders, opiate overdose, depression, smoking, alcoholism, sexual dysfunction, shock, stroke, spinal damage and head trauma.
• the structure activity relationships of this series of compounds is reviewed in J. Medicinal Chemistry, 1993, 36, 2833 and their effect on food consumption in obese Zuker rats is described in J. Medicinal Chemistry 1993, 36, 2842.
• the present invention provides for the use of a compound for the preparation of a medicament for use in the treatment of pruritus in a human or animal, wherein said compound is:
• n 0 or 1
• X is C( ⁇ O), CH(OH), CH ⁇ CH, S, O, or NR 8 ,
• R 8 is H, C 1 -C 4 alkyl or C 1 -C 4 alkanoyl
• Z is C( ⁇ O), CH(OH), or CH ⁇ CH
• W is O or S
• R 5 is C 1 -C 3 alkylthio, nitro, amino, trifluoromethyl, hydroxy, or R 6 ;
• R 6 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or halogen;
• R 7 is H or methyl
• R 2 is H, C 1 -C 4 alkyl, or C 2 -C 6 alkenyl
• R 3 is C 1 -C 4 alkyl or C 2 -C 6 alkenyl
• R 4 is H, hydroxy, C 1 -C 3 alkoxy, C 1 -C 12 alkanoyloxy, or ##STR3## or a pharmaceutically or veterinarily acceptable salt thereof; with the limitation that when X or Z is CH(OH) or C( ⁇ O), n is other than 3; or
• R 2 is H, C 1 -C 4 alkyl or C 2 -C 6 alkenyl
• R 3 is C 4 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 4 alkyl substituted C 4 -C 8 cycloalkyl, C 1 -C 4 alkyl substituted C 4 -C 8 cycloalkenyl or thienyl;
• Z is CH(OR 4 ), (C ⁇ O) or a bond
• R 4 is hydrogen, C 1 -C 6 alkyl, ##STR5##
• R 5 is C 1 -C 4 alkyl or ##STR6##
• n is 1, 2 or 3; or a pharmaceutically or veterinarily acceptable salt thereof; or
• R 2 is H, (C 1 -C 5 ) alkyl, or (C 2 -C 6 ) alkenyl;
• R 3 is H, (C 1 -C 10 ) alkyl, (C 3 -C 8 ) cycloalkyl; (C 3 -C 10 ) alkenyl, (C 3 -C 8 ) cycloalkyl-(C 1 -C 3 ) alkyl, phenyl, (C 5 -C 8 ) cycloalkenyl, (C 5 -C 8 ) cycloalkenyl-(C 1 -C 3 ) alkyl, or phenyl-(C 1 -C 3 )alkyl;
• R 4 is H, (C 3 -C 8 ) cycloalkyl, (C 1 -C 10 ) alkyl, (C 3 -C 10 ) alkenyl, (C 3 -C 8 ) cycloalkyl-(C 1 -C 3 )alkyl, phenyl or phenyl-(C 1 -C 3 ) alkyl;
• R 5 is H, (C 1 -C 10 )alkyl (C 1 -C 10 )alkanoyl, C(O)CH--[(CH 2 ) 3 NHC(NH)NHNO 2 ]--NHC(O)W, C(O)NH(C 1 -C 10 )alkyl, [C(O)--(CH 2 ) m C(O)] q R 6 , or [C(O)(CH 2 ) m NHC(O)] q- R 6- ,
• W is (C 1 -C 10 )alkyl, O(C 1 -C 10 )alkyl, (C 1 -C 4 alkyl)-NHC(O)(C 1 -C 6 )-alkyl, or (C 1 -C 4 alkyl)C(O)NHB, where B is (C 1 -C 10 )-alkyl, phenyl or phenyl-(C 1 -C 3 ) alkyl;
• R 6 is OR 7 ; NHR 7 , OCH 2 C(O)NR 8 R 9 , O(C 1 -C 4 )alkyl)OC--(O)R 10 , (C 1 -C 10 )alkyl or NHCHR 11 C(O)R 12 -,
• R 7 is H, (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl-C 1 -C 3 )alkyl or (CH 2 ) m C(O)NR 8 R 9- ,
• R 8 is H, or (C 1 -C 10 )alkyl
• R 9 is H, or (C 1 -C 10 )alkyl
• R 10 is (C 1 -C 10 ) alkyl, (C 3 -C 8 ) cycloalkyl, or ##STR8##
• R 11 is H, (C 1 -C 10 )alkyl, or phenyl-(C 1 -C 3 )alkyl;
• R 12 is OR 13 or NR 13 R 14 ;
• R 13 is H or (C 1 -C 10 )alkyl
• R 14 is H or (C 1 -C 10 )alkyl
• n 1-3;
• R 2 is H, C 1 -C 5 alkyl or C 2 -C 6 alkenyl
• R 3 is H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, phenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl or phenyl-substituted C 1 -C 3 alkyl;
• A is OR 4 or NR 5 R 6 ;
• R 4 is H, C 1 -C 10 alkyl C 2 -C 10 alkenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl or phenyl-substituted C 1 -C 3 alkyl;
• R 5 is H or C 1 -C 3 alkyl
• R 6 is H, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, cycloalkyl, phenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl, phenyl-substituted C 1 -C 3 alkyl, or (CH 2 ) q --B; or
• R 5 and R 6 are each CH 2 which together with N form a 4- to 6-membered heterocyclic ring;
• B is ##STR10## or NR 7 R 8 wherein: R 7 is H or C 1 -C 3 alkyl;
• R 8 is H, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, cycloalkyl, C 5 -C 8 cycloalkenyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl, phenyl or phenyl-substituted C 1 -C 3 alkyl; or
• R 7 and R 8 are each CH 2 which together with N form a 4- to 6-membered heterocyclic ring
• W is OR 9 , NR 10 R 11 , or OE;
• R 9 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl or phenyl-substituted C 1 -C 3 alkyl;
• R 10 is hydrogen or C 1 -C 3 alkyl
• R 11 is hydrogen, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, phenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, phenyl-substituted C 1 -C 3 alkyl, or ##STR11## or R 10 and R 11 are each CH 2 which together with N form a 4- to 6-membered heterocyclic ring;
• R 12 is C 1 -C 3 alkyl substituted methylene
• R 13 is C 1 -C 10 alkyl
• D is OR 14 or NR 15 R 16- ;
• R 14 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, or C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl or phenyl-substituted C 1 -C 3 alkyl;
• R 15 is H, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, phenyl, phenyl-substituted C 1 -C 3 alkyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl or C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl;
• R 16 is H or C 1 -C 3 alkyl
• R 15 and R 16 are each CH 2 which together with N form a 4- to 6-membered heterocyclic ring;
• Y is OR 17 or NR 18 R 19 ;
• R 17 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl, or phenyl-substituted C 1 -C 3 alkyl;
• R 18 is hydrogen or C 1 -C 3 alkyl
• R 19 is hydrogen, C 1 -C 10 alkyl, C 3 -C 10 alkenyl, phenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, cycloalkyl-substituted C 1 -C 3 alkyl, C 5 -C 8 cycloalkenyl-substituted C 1 -C 3 alkyl, or phenyl-substituted C 1 -C 3 alkyl; or
• R 18 and R 19 are each CH 2 which together with N form a 4- to 6-membered heterocyclic ring;
• n 0-4;
• n 1-4;
• a particularly preferred group of compounds for use in the present invention are compounds of the formula 5: ##STR13## and pharmaceutically or veterinarily acceptable salts thereof wherein in Formula 5 above:
• R 20 is H or C 1 -C 4 alkanoyl
• R 21 is C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl(C 1 -C 6 )alkyl, C 5 -C 8 cycloalkenyl(C 1 -C 6 )cycloalkyl, or a group of the formula --(CH 2 ) n --G--A 1 ;
• n 1, 2 or 3;
• G is C ⁇ O, CH(OH),O, or a direct bond
• a 1 is C 3 -C 8 cycloalkyl, phenyl, which may optionally be substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, or A 1 is thienyl, furyl, or pyridyl.
• the invention also provides for a method of treating pruritus, in a human or animal which comprises administering a therapeutically or prophylactically effective amount of a compound of the formula 1, 2, 3, 4 or 5 as defined above, or a pharmaceutically or veterinarily acceptable salt thereof.
• the piperidines of this invention form pharmaceutically or veterinarily acceptable acid addition salts with a wide variety of inorganic and organic acids.
• the particular acid used in salt formation is not critical; however, the corresponding salt that is formed must be substantially non-toxic to animals.
• Typical acids generally used include sulphuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinamic, benzoic, ascorbic and related acids.
• the piperidines additionally form quaternary ammonium salts, for example, with a variety of organic esters of sulphuric, hydrohalic and aromatic sulphonic acids.
• the compounds of the invention contain one or more asymmetric centres and thus they can exist as enantiomers and diastereomers.
• the invention includes the use of both the separated individual isomers as well as mixtures of isomers.
• Particularly preferred compounds for use in the treatment of pruritus include compounds of the formula (5) above wherein R 20 is H or COCH 3 and wherein R 21 is C 2 to C 8 alkyl, particularly n-hexyl or 2-methyl-pentyl, or C 1 -C 6 alkyl substituted by C 3 -C 8 cycloalkyl, particularly cyclohexylethyl.
• the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a compound of the invention.
• a pharmaceutical or veterinary formulation comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient and a compound of the invention.
• Such compositions will contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
• the methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant.
• Such formulations are prepared in a conventional manner in accordance with standard veterinary practice.
• capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier additionally containing a disintegrating agent and/or binder such as starch, lactose, talc or magnesium stearate, etc.
• Oral drenches are prepared by dissolving or suspending the active ingredient in a suitable medium.
• Pour-on or spot-on formulations may be prepared by dissolving the active ingredient in an acceptable liquid carrier vehicle such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan-2-ol.
• pour-on, spot-on or spray formulations can be prepared by encapsulation, to leave a residue of active agent on the surface of the animal.
• Injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood.
• Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristrate and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol formal.
• the formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.1 to 10% by weight of the active ingredient.
• compositions will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal.
• typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.
• Preferably the range is 0.1 to 10 mg per kg.
• compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient.
• unit dosage form refers to physically discreet units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
• the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses.
• the invention also provides a veterinary formulation comprising a compound of the formula 1, 2, 3, 4 or 5, as defined above, together with a veterinarily acceptable diluent or carrier.
• Such formulations include in particular ointments, pour-on formulations, spot-on formulations, dips, sprays, mousse, shampoo, collar and powder formulations.
• the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
• the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier.
• the compounds of the invention are prepared using the procedures described in GB-A-1525584, EP-A-0287339, EP-A-0506468, EP-A-0506478 or in J. Medicinal Chemistry 1993, 36, 2833.
• the following examples are illustrative of the preparation of typical examples:
• Nuclear magnetic resonance (NMR) spectral data were obtained using a Bruker AC300 or AM300 spectrometer, the observed chemical shifts ( ⁇ ) being consistent with the proposed structures.
• Mass spectral (MS) data were obtained on a Finnigan Mat. TSQ 7000 or a Fisons Instruments Trio 1000 spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass.
• HPLC means high performance liquid chromatography.
• Room temperature means 20 to 25° C.
• N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution.
• the reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained.
• the aqueous phase was extracted with dichloromethane (3 ⁇ 75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2 ⁇ 50 ml).
• the aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3 ⁇ 40 ml).
• Enantiomeric purity was determined using a ChiralpakTM AD column 25 cm ⁇ 0.46 cm; Flow 1 ml min -1 ; employing UV detection at 254 nm; eluent hexane:propan-2-ol (90:10)+1% diethylamine (w/v).
• 3-(2-Thiophene)propanoic acid (220 mg, 1.4 mmol) [prepared in direct analogy with Toth et al., Synth. Commun. 1995, 25, 3067], 1-hydroxybenzotriazole (204 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 2.0 mmol) and dimethylformamide (50 ml) were stirred together at room temperature until all the solids had dissolved. ( ⁇ )-4-(3-hydroxyphenyl)-trans-3,4-dimethylpiperidine (300 mg, 1.5 mmol) was added and the reaction mixture allowed to stir at room temperature for 18 hours.
• reaction mixture was diluted with water (25 ml) and extracted with diethyl ether (25 ml).
• the diethyl ether extract was dried (Na 2 SO 4 ) and concentrated in vacuo to produce a clear colourless oil.
• the crude product was purified by silica (10 g) column chromatography, eluting with ethyl acetate. The appropriate fractions were combined and concentrated in vacuo to yield 300 mg of a white solid. This solid was then dissolved in anhydrous tetrahydrofuran (25 ml) and a 1M solution of lithiumaluminium hydride in diethyl ether (10 ml) was added to the solution.
• the compounds of the invention are evaluated for their activity as antipruritic agents by measuring their ability to inhibit the hind leg scratching behaviour induced in rats by the administration of a known pruritogenic agent. These studies are based on the procedure described by Berendsen and Broekkamp in the European Journal of Pharmacology, 1991, 194, 201. The test is performed as follows:
• the test compound is administered to the test animals by subcutaneous injection in an aqueous micelle formulation.
• the test compound is prepared in the following manner.
• the compound is dissolved in vehicle (composition v/v %: glycerol formal, 24; tween 80, 17; benzyl alcohol, 1.5 and purified water to 100) then seven parts purified water is added to three parts vehicle to give the aqueous micelle formulation.
• vehicle composition v/v %: glycerol formal, 24; tween 80, 17; benzyl alcohol, 1.5 and purified water to 100
• the compounds can be administered pre- or post-challenge or may be co-administered with the pruritogenic challenge.
• b is the mean hindleg scratching score of treated and challenged rats.
• Antipruritic activity was also demonstrated in dogs suffering from flea allergy dermatitis.
• Administration by subcutaneous injection significantly reduced scratching behaviour at a dose level of 1-10 mg/kg.

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• 1997
  • 1997-11-28 GB GBGB9725114.4A patent/GB9725114D0/en not_active Ceased
• 1998
  • 1998-11-12 EP EP98309255A patent/EP0938898A3/en not_active Withdrawn
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